| Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks. | |
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MedLine Citation:
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PMID: 17119966 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Thymidylate synthase (TS) over-expression is widely accepted as a major molecular mechanism responsible for 5-fluorouracil (5-FU) and tomudex (TDX) resistance. In this study, the importance of TS in 5-FU and TDX resistance was evaluated. METHODS: The sensitivity of TS-over-expressing 5-FU (3) and TDX (3) resistant cell lines to 5-FU and TDX was analysed. The cross-resistance between 5-FU and TDX resistant cell lines was determined. The relationship between p53 and NF-kappaB status and the sensitivity to 5-FU and TDX was evaluated. RESULTS: Compared to relevant parental sensitive cell lines, the 5-FU resistant cell lines were highly cross-resistant to TDX (over 20,000-fold). In contrast, over-expression of TS did not significantly confer 5-FU resistance on the TDX resistant cell lines (0.8- to 1.3-fold). Thymidine (20 microM) rescue induced TDX resistance in TDX sensitive cell lines (over 10,000-fold) but only moderately influenced 5-FU sensitivity in 5-FU sensitive cell lines (1.1- to 2.4-fold). Uridine moderately protected one cancer cell line (RKO) from 5-FU-induced, but not TDX-induced, cytotoxicity. NF-kappaB transfected MCF-7 and p53 knockout HCT116 cells were resistant to 5-FU (4.4- and 2.4-fold, respectively) but not to TDX. TS protein expression in NF-kappaB transfected and p53 knockout cell lines was comparable to the relevant parental cell lines. CONCLUSION: In some cancer cell lines, TS-independent molecular events may play a key role in 5-FU resistance. Loss of p53 function and NF-kappaB over-expression may be involved in TS-independent 5-FU chemoresistance in some cancer cell lines. |
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Authors:
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Weiguang Wang; Howard L McLeod; James Cassidy; Elaina S R Collie-Duguid |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-11-22 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 59 ISSN: 0344-5704 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2007 May |
Date Detail:
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Created Date: 2007-03-20 Completed Date: 2007-05-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 839-45 Citation Subset: IM |
Affiliation:
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Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wolverhampton, WV1 1SB, UK. w.wang2@wlv.ac.uk |
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| MeSH Terms | |
Descriptor/Qualifier:
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Antimetabolites, Antineoplastic
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pharmacology* Drug Resistance, Neoplasm* Fluorouracil / pharmacology* Humans NF-kappa B / metabolism Quinazolines / pharmacology* Thiophenes / pharmacology* Thymidine / pharmacology Thymidylate Synthase / metabolism* Transfection Tumor Cells, Cultured Tumor Suppressor Protein p53 / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/NF-kappa B; 0/Quinazolines; 0/Thiophenes; 0/Tumor Suppressor Protein p53; 112887-68-0/raltitrexed; 50-89-5/Thymidine; 51-21-8/Fluorouracil; EC 2.1.1.45/Thymidylate Synthase |
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